| 1. |
- Jallow, Muminatou, et al.
(författare)
-
Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
-
Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
|
|
| 2. |
- Benn, Diana E, et al.
(författare)
-
Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.
- 2006
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:3, s. 827-36
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations.DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland.MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined.RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008).CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.
|
|
| 3. |
- Goldhahn, Jörg, et al.
(författare)
-
Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis
- 2008
-
Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 43:2, s. 343-347
-
Tidskriftsartikel (refereegranskat)abstract
- Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care. © 2008 Elsevier Inc. All rights reserved.
|
|
| 4. |
- Jacoby, Charles A., et al.
(författare)
-
Vertical distribution, behavior, chemical composition and metabolism of Stauroteuthis syrtensis (Octopoda : Cirrata) in the northwest Atlantic
- 2009
-
Ingår i: Aquatic Biology. - : Inter-Research Science Center. - 1864-7782 .- 1864-7790. ; 5:1, s. 13-22
-
Tidskriftsartikel (refereegranskat)abstract
- The cirrate octopod Stauroteuthis syrtensis is a mesopelagic species commonly collected in the North Atlantic. Individuals were observed at depths > 600 m and typically within 100 m of the bottom in three similar to 900 m deep canyons indenting the southern edge of Georges Bank. When first sighted, most octopods were floating passively with their webbed arms gathered into a small ball. When disturbed, they expanded their webs to form a 'balloon' shape, swam slowly by Sculling their fins, pulsed their webs like medusae and, in some cases, streamlined their arms and webs and moved away smoothly by rapidly sculling their fins. The bodies of 9 octopods comprised 92 to 95 % water, with tissue containing 9 to 22 % carbon (C) and 2 to 4 % nitrogen (N). These values were similar to those reported for medusae and ctenophores. Oxygen (O(2)) consumption rates of 4.6 to 25.8 mu mol 02 g(-1) C h(-1) were within ranges reported for medusae, ctenophores, and deep-water cephalopods. The stomachs of S. syrtensis, dissected immediately after capture, contained only the calanoid copepod Calan us finmarchicus. Calculations indicated that S. syrtensis need 1.3 to 30.1 ind. d(-1) of C. finmarchicus to meet their measured metabolic demand. Excretion rates (0.3 to 12.4 mu g NH(4)(+) g(-1) C h(-1) and 0.06 to 4.83 mu g PO(4)(3-) g(-1) C h(-1)) were at least an order of magnitude lower than rates reported for other octopods or gelatinous zooplankters. O:N ratios (11 to 366) suggested that S. syrtensis catabolized lipids, which may be supplied by C. finmarchicus. Vertical distribution, relatively torpid behavior and low metabolic rates characterized S. syrtensis as a benthopelagic and relatively passive predator on copepods.
|
|
| 5. |
- Mangano, Valentina D, et al.
(författare)
-
Lack of association of Interferon Regulatory Factor 1 with severe malaria in affected child‐parental trio studies across three African populations
- 2009
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:1, s. e4206-
-
Tidskriftsartikel (refereegranskat)abstract
- Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.
|
|
| 6. |
- Marsh, David
(författare)
-
The Grassmannian sigma model in SU(2) Yang-Mills theory
- 2007
-
Ingår i: Journal of Physics A: Mathematical and Theoretical. - : IOP Publishing. - 1751-8113 .- 1751-8121. ; 40:32, s. 9919-9928
-
Tidskriftsartikel (refereegranskat)abstract
- Spin–charge separation in pure SU(2) Yang–Mills theory was recently found to involve the dynamics of an O(3) nonlinear sigma model and, seemingly, a Grassmannian nonlinear sigma model. In this paper we explicitly construct the Grassmannian sigma model of the form appearing in the spin–charge separated SU(2) theory through a quaternionic decomposition of the manifold, thus verifying its relevance in this context. The coupling between this model and the O(3) nonlinear sigma model is further commented upon.
|
|
| 7. |
- Siskind, David E., et al.
(författare)
-
Decreases in atomic hydrogen over the summer pole : Evidence for dehydration from polar mesospheric clouds?
- 2008
-
Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 35:13
-
Tidskriftsartikel (refereegranskat)abstract
- Observations from the Sounding of the Atmosphere with Broadband Emission Radiometry (SABER) instrument on the NASA/Thermospheric Ionosphere Mesosphere Energetics and Dynamics satellite show a surprising decrease in the inferred atomic hydrogen (H) over the polar regions in the lowermost thermosphere during the summer. This contrasts with predictions by global models that H should peak in this region at this time. We suggest the decrease is a consequence of the sequestering of the water vapor by the formation of polar mesospheric clouds (PMCs) that redistributes the H2O thus reducing the chemical source of H. This decrease is more pronounced in the Northern rather than the Southern summer which is roughly consistent with the known morphology of PMCs. A model calculation which includes a PMC parameterization gives good qualitative agreement with the data suggesting that this process should be considered in global models of the coupling between the middle and upper atmosphere. Copyright 2008 by the American Geophysical Union.
|
|
